Oxidative stress is implicated in a wide variety of diseases, including but not limited to age-related macular degeneration (AMD), diabetes, atherosclerosis, aging, and neurodegeneration. The biochemical markers of oxidative stress, including lipid peroxidation, DNA base hydroxylation, and protein modification, result primarily from reaction with the highly reactive hydroxyl radical, OH7, itself a product of iron-catalyzed reactions, with oxygen species. While iron is an essential and beneficial component of healthy cells, this deleterious reactivity suggests that any free iron in the cell will cause significant damage. Inhibiting metal-promoted oxidative stress is therefore a promising strategy for treating a number of diseases, especially those where normal metal ion homeostasis is impaired or where aberrant metal accumulation is documented, as is the case for AMD. Generalized iron chelation could protect against oxidative damage, but could also be detrimental if iron needed for metabolic processes is removed. We are designing chelating agents (prochelators) that are active only when needed: they selectively sequester and inactivate iron only in cells undergoing oxidative stress, thereby limiting oxidative damage in these cells. These chelators are chemical modifications of salicylaldehyde isonicotinoyl hydrazone (SIH), which we have found able to protect cultured retinal pigment epithelial cells (RPE) from death induced by a wide variety of insults. We propose herein to test in RPE cells the ability of several modified SIH molecules to decrease the labile iron pool selectively when cells are experiencing oxidative stress, and to determine whether the chelators increase cell viability. Preliminary results suggest that these prochelators are activated by oxidative stress both in the test tube and in RPE cells, and that they can protect cultured RPE cells from oxidant induced death. The goal of this proposal is to identify prochelators with the optimal characteristics: maximal RPE protection with minimal toxicity. These studies will lay the groundwork for future prochelator testing in mouse retinal degeneration models. It is hoped that these studies will lead to a new preventative agent for patients with early AMD.